A series of European countries have paused their roll out of the Oxford-AstraZeneca COVID-19 vaccine.
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Rarely has an immunisation program been more important to the wellbeing of a population. With so much at risk, confidence in the available vaccines and the willingness to receive them is paramount. Past research has shown that vaccine scares, legitimate or not, have derailed immunisation programmes. A country level decision to suspend a vaccine program due to safety concerns does affect confidence globally, but it is only through acknowledgement of safety fears, together with prompt and scientifically based responses that confidence can be sustained. Critically, communication must be timely, transparent and internationally consistent, to maintain and build the public trust without which any rollout however logistically effective will fail.
Bleeding is the most likely outcome for patients with thrombocytopenia. However information is emerging that the there are reports of a very rare condition. Thrombocytopenia (low blood platelets) is usually associated with a tendency to bleed, however there are rare situations where low platelets is associated with higher tendency for blood clotting. For example, this happens with the drug heparin which is blood thinner. In rare circumstances heparin results in causing clotting. Heparin induced thrombocytopenia (HIT) can be non-immune which is mild, or immune which is severe. The immune HIT can be associated with severe clotting tendency.
Let’s wait to see whether the association between thrombocytopenia and clotting with AstraZeneca Covid vaccine is HIT-like. If so, it seems to be very rare. It raises the possibility that certain patient characteristics may be identified to minimise the risks for a very small number of people who may develop this condition with the vaccine.
Like most pharmacovigilance signals the events of thrombocytopenia and clotting in this case is an evolving story, more information becomes available with time.
The concern expressed in the document1 produced by the Paul Ehrlich Institute in Germany relates to a specific type of event (severe cerebral venous thrombosis) in a subgroup of vaccinated individuals in Germany below the age of 50 years, where the overall risk/benefit of vaccination might be viewed differently. That is, where the potential benefit to the vaccinated individual may be lower due to a smaller risk of severe disease or death following infection with SARS-CoV-2.
It is entirely appropriate to investigate safety signals in this manner and established pharmacovigilance processes are being followed, including at the national level in Germany and within the EU (via the Pharmacovigilance Risk Assessment Committee at the European Medicines Agency). In this respect a thorough assessment will be undertaken at both the aggregate level (observed versus expected cases) and the individual level (temporal relationship), as the document states. The clinical trial data from the Oxford/AstraZeneca vaccine will be carefully reviewed as will emerging data from other vaccines. Overall the regulators will use data from various sources combined with an understanding of the basic science to determine if the product labelling (the SmPC) requires modification. There are a number of statistical traps that need to be navigated past during this process. For instance, the more that the data are sliced and diced, the more likely it is that clusters will emerge. This is most commonly seen in subgroup analyses. If there is no excess overall, then if an excess of cases is found in a subgroup, then typically there must a deficit of cases elsewhere. It will also be important to explore various time windows and the experience across all countries where vaccination has commenced.
Although the document raises questions around re-evaluating the risk/benefit in those under 50 years of age, even if a causal relationship between the vaccine and venous thrombosis were subsequently determined, it is unclear how these emerging data impact the original risk/benefit in the elderly populations that are being prioritized for vaccination currently. Unless there are alternative vaccines available in sufficient quantity to avoid delay, then it seems likely that a temporary suspension will lead to more cases of severe disease and death than would otherwise have been the case.
The benefits of the vaccine in preventing COVID-19, with its associated risk of hospitalisation and death, far outweigh the risks of side effects. People should go and get their COVID-19 vaccine when asked to do so.
It is still the case that it has not been confirmed the reported blood clots were caused by the COVID-19 Vaccine AstraZeneca. Blood clots can occur naturally and are not uncommon.
Our role is to continually monitor safety during widespread use of a vaccine. We have in place a proactive strategy to do this. We also work closely with our public health and international partners in reviewing the effectiveness and impact of the vaccines to ensure the benefits continue to outweigh any possible side effects.
We now find ourselves in a predicament with regard to programmes to prevent COVID by vaccination across Europe and globally.
The AstraZeneca vaccine is highly effective at preventing severe COVID even after just one dose and even in elderly vulnerable people. Supplies are ramping up – somewhat slower than originally hoped – but rapidly nonetheless – in many countries across the world.
Other vaccines are, so far, less widely available and tend to be more expensive and more difficult to handle and distribute.
In the UK, where more doses of the vaccine have been given than in any other European country – and where a well-established safety monitoring and adverse event reporting system is in place – no increase in the number of cases of blood clotting illnesses above what would normally be expected has been reported.
In a few other countries small numbers of cases of people who have had blood clots – some of them fatal illnesses – have occurred in people who were recently vaccinated. Again, the overall numbers do not appear to be higher than is normally expected when no vaccine programme is being rolled out. Nevertheless these cases have generated concerns sufficient to lead to the temporary suspension of the use of the AZ vaccine in several of these countries as well as other countries in which no such cases have been reported.
Details of these cases are now being studied by the medicines regulatory authorities. So far their opinions have been reassuring. We expect to hear more from the European Medicines Agency on Thursday and we may hear more from the UK regulator too in the coming days.
What should people make of all this in the meantime?
We know the risks of COVID are real – both of severe illness in the short term and of long term problems among some who recover from the acute infection. We know the AZ vaccine prevents these problems and risks and that, used widely, it can help us overcome the pandemic and all its consequences. We know that rolling out the vaccine fast and at scale is important for that protection. We know that the vaccine causes no severe permanent side-effects or that, at the very worst, any such side-effects are so rare that they are proving almost impossible to detect despite millions of doses of vaccine having been administered. We should understand the need to investigate any concerns that arise and feel reassured that this is being done thoroughly. While that goes on, we should allow our policy decisions and our personal decisions to be driven by what we do know and not what we don’t.
A variety of illnesses related to blood clotting occur very frequently, including heart attacks, strokes, leg vein clots (DVT) and clots going into the lungs (PE) as well as some rare conditions. Because blood clotting illnesses are common, it is expected that many people, out of the millions vaccinated, will suffer one of these by chance after receiving a COVID-19 vaccine. Many different things influence the likelihood of illness related to blood clots: some people are born with genetic conditions that make them more susceptible to blood clots and some types of medication, such as the combined oral contraceptive pill, can increase the risk. Inflammation in the blood can increase the risk of blood clots and this is one reason why COVID-19 is associated with an increased risk of blood clots. Vaccines generally cause temporary and weak inflammation so it is theoretically possible that blood clots will occur slightly more frequently after a vaccine in susceptible people but these events may have happened anyway at a later date and would be much more likely if someone became seriously unwell with COVID-19. So having the vaccine should lower the risk of serious illness, including blood clots, and this has been the experience with the flu vaccine. Regardless of whether or not people have just had a vaccine, they should call for help if they have symptoms of a heart attack or stroke since early treatment is essential and it is much better for patients as well as the health service if treatment is given as soon as possible.
The current suspension of the Oxford/AstraZeneca COVID vaccine in Germany relates to a cluster of 7 cases of blood clotting in the blood vessels draining blood from the brain. This was associated with a fall in the blood platelets, the cells that form blood clots and can get used up in a blood clotting condition known as thrombotic thrombocytopenia purpura (TTP). This is a rare but serious condition with many different triggers and each case requires careful investigation to explore this. One of the challenges for scientists is that it is a statistical inevitability that rare conditions can occur in clusters, making it hard to know early on whether any cluster of events is due to chance or due to a particular cause. With so many countries vaccinating millions of people, we can expect to see clusters of rare conditions that potentially raise concern about vaccine safety. So far it is reassuring that similar events have not been reported in the UK after many millions of vaccinations and this is something that will be monitored closely using the notification system to the MHRA.
With the role out of COVID-19 vaccines being carried out both rapidly and in such high volumes, we were always going to be in the position where signals of possible safety issues would arise. In itself, this is not a bad thing; it’s a sign that our long-established early warning system for finding possible problems with medications is working well. To be clear, this is unlikely to be the only safety signal we will be faced with over the coming months and what matters is how we respond to them as they come along. This needs to be done with complete openness, according to tried and tested methods, and with our focus constantly on how the totality of evidence informs the balance of risks and benefits of vaccination.
Anyone with a natural tendency to be cautious will understandably question whether we should indeed pause the role out of the AZ vaccine at this point, but I believe this is overly conservative, and we must also take into account the huge benefit in terms of protecting against COVID-19 disease that we know these vaccines confer. The harm from suspending a vaccination programme comes in two main forms. Firstly, by withholding the vaccine we are denying potentially millions of people the real, well characterised and considerably large benefit it brings. Unfortunately, at a point in time when infection rates are again rising in many countries, people who remain unvaccinated will remain at risk of COVID-19 infection and we know a proportion of those infected will develop serious COVID-19 illness and some will die. Ironically some of this the serious illness that could be avoided through vaccination involves clotting problems, a now well characterised aspect of COVID-19. But possibly even more damaging at this stage is the knock in vaccine confidence that people will feel. Confidence is easily lost and less easily regained.
For almost a year now, the medicines regulators have been planning meticulously how to handle these situations. The cluster of individual case reports of clotting problems are themselves unlikely to help us decide whether the vaccine was the cause. Clotting problems happen fairly regularly and are a normal part of the wide landscape of illnesses we face as humankind. To decide whether these specific cases may have been caused by the vaccine, we need to rely on other sources of data and a process known as signal strengthening. The UK’s medicines regulator, the MHRA, along with others like the EMA in the EU have well established protocols for this, including cross-checking whether medical problems seen in clusters of case reports appear to be occurring at a higher rate than normal in the population. All indications so far are that clotting problems are no more common in people who have received the vaccine than we would normally expect, and if anything, we are seeing less of them than usual. Clotting problems were not seen in the randomised trials of the vaccine, so the safety signal gains no further strength there either, and along the pathway of signal strengthening, these observations should tend to de-escalate concerns to some extent.
We certainly ought not to rest here, and further formal studies of the association between COVID-19 vaccines and clotting will be done in the next few weeks and months. More will emerge about the cluster of cases already known about, such as we see today from Germany and I have no doubt that further cases will be reported, given the publicity and the large number of people who have been vaccinated. We will need to continue to evaluate these and be open to changing our conclusions. But for now, I see little evidence that the safety profile of the vaccine is any different from our original understanding. I see some signs that the safety signal of clotting may be a chance finding, and I remain convinced of the tremendous benefits the vaccine brings.
The first concerns that were expressed related to blood clotting in general particularly four strokes and clocks on the lungs. These are very well known effects of the virus that causes COVID-19. More recent concerns have related to another type of blood coagulations disorder called thrombocytopenia. This also is well known to occur in patients who get COVID-19.
Further detailed concerns from Germany relate to a much rarer form of thrombosis in the brain.
It still remains the case that a very likely explanation of at least some of the clotting disorders seen are a result of Covid-19 rather than the vaccine.
There are published papers that make clear that these problems definitely occur in COVID-19 and there is no doubt that all the vaccines in use prevent that disease. Hence the risk and benefit balance for the AstraZeneca vaccine remains clearly in favour of its benefits.
A number of published papers have shown thrombocytopenia, which is a key feature of the German and Danish concerns, as occurring in patients with Covid, e.g.
An overview of blood coagulation disorders which covers clotting and to a lesser degree thrombocytopenia, is given at: https://www.karger.com/Article/FullText/512007
This statement is made in the NEJM paper below “On admission, lymphocytopenia was present in 83.2% of the patients, thrombocytopenia in 36.2%, and leukopenia in 33.7%”:
The bad outcomes associated with thrombocytopenia in Covid are given in: https://ehoonline.biomedcentral.com/articles/10.1186/s40164-020-00172-4
The, said to be very much rarer, cerebral Venous Sinus Thrombosis may be more common than thought [https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.116.013617], and is definitely described in Covid before vaccines were available: https://www.sciencedirect.com/science/article/pii/S2214751921000037 and although the Germans think their cases have a different mechanism to simple thrombocytopenia, it seems very likely that this different mechanism could also be caused by Covid.
The situation is that we know that Covid causes major problems to the body’s coagulation systems, and many of these are very common in Covid, some with serious outcomes. Hence, even if there were a problem, acknowledged to be very rare with the AZ vaccine, the overall benefit would be so much greater than any speculative harm.